Brain damage occurs in over 60% of chronic alcoholics. The causes and preventability of this damage, however, are poorly understood. The general goal of our research has been to evaluate the factors that lead to alcohol-induced degeneration of the nervous system in experimental animals. It is generally agreed that at least one type of alcohol-induced brain damage, Wernicke-Korsakoff's encephalopathy, is due to alcohol-induced thiamine deficiency. We have therefore studied neuronal degeneration in thiamine deficient rats. The brains of these rats demonstrate a loss of neurofilament and microtubule associated protein. Since these proteins are known to be selectively degraded by calcium activated proteolysis, this observation suggests that thiamine deficiency may lead to an increase in intracellular calcium ion, which then triggers calcium activated proteolysis of these proteins. To directly investigate the role of ionized calcium in neuronal degeneration we have studied the conditions and consequences of increasing intracellular calcium ion in the squid nervous system. We have demonstrated that increasing calcium ion in nerve cell bodies and axon causes activation of a calcium-dependent protease which then breaks down neurofilament proteins.